Adult hippocampal neurogenesis is orchestrated by neural stem cell (NSC) activity. Some associations exist between autophagy and neurogenesis, yet much remains unknown about autophagic regulation of adult neurogenesis. This thesis interrogates the requirement and role of Beclin1 and Atg5, two regulators of autophagy, in the formation of adult hippocampal neurons. To examine adult brain NSCs, the experiments presented in the first objective of this thesis test the ability to isolate adult NSCs using flow cytometry and a DNA-binding dye, DyeCycleViolet. While adult NSCs could not be isolated from the adult neurogenic niches using this methodology, it was effective in isolating endothelial cells. This provided valuable insight on the use of DNA-binding dyes and a new method for isolation of brain endothelial cells. The next objective determines the role of Beclin1 in adult NSCs and their progeny using an inducible model. Beclin1 loss in Nestin-expressing hippocampal NSCs resulted in reduced proliferation, autophagy, and adult neurogenesis within one month. Single-cell RNA sequencing and other methods illuminated that loss of Beclin1 resulted in mitosis reduction, disrupted mitotic regulation of chromatin maintenance, and induction of DNA damage. The final objective first tests whether Beclin1 loss results in similar deficits within GLAST-expressing NSCs and progeny. This model mirrored neurogenesis deficits and requirement of Beclin1 in mitosis and DNA maintenance. Next, to test whether this phenotype occurs with other autophagy proteins, Atg5 was removed from GLAST NSCs. This resulted in reduced autophagy and a transient decrease in neurons in the absence of any effect on NSC proliferation. Thus, proliferation deficits are unique to Beclin1 loss and do not underlie reduced adult hippocampal neurogenesis after Atg5 removal. This work demonstrates a novel discovery of mitosis regulation in adult NSCs by Beclin1, and individual roles of Beclin1 and Atg5 in neurogenesis.

While antiretroviral therapy (ART) regimens have significantly decreased the mortality rate in patients with HIV-1 infection and subsequent opportunistic infections, the co-morbidities continue to rise. Some of these co-morbidities include cardiomyopathies, metabolic dysfunction, accelerated aging, and most notably, neurocognitive deficits. HIV-1 associated neurocognitive disorders (HAND) denote a spectrum of neurocognitive deficits that are either asymptomatic in nature (asymptomatic neurocognitive impairments, ANI), mild to moderate in intensity (mild neurocognitive disorders, MND), or robust in nature (HIV-associated dementia, HAD). Thanks to the development of ART regimens, the incidence of HAD dramatically decreased. However, the emergence of ANI and MND continues to increase in the HIV-1 patient population. While the multifaceted nature behind the central nervous system (CNS) neuropathology of HIV-1 infection is not completely understood, dysregulated blood-brain barrier (BBB) integrity and the “Trojan-Horse” type mechanism of HIV-1 infection have been proposed as the cellular mechanisms underlying HAND. HIV-1 infects CD4+ T-lymphocytes and monocytes in the peripheral circulatory system. After these infected cells cross the BBB into the CNS, they release toxic viral proteins and viral particles onto microglia and astrocytes. These glial cells become activated, and release a plethora of inflammatory cytokines that further damage neurons via dysregulated neurotransmitter homeostasis, synaptodendritic damage, and calcium-mediated apoptotic pathways. At the same time, the virus may establish a state of latency in these microglia, perivascular macrophages, and astrocytes, which would allow for the long-term persistence of HIV-1 in the CNS. Recently, several studies have demonstrated that neural stem cells (NSCs) are capable of being productively and latently infected with HIV-1. This may be due to the fact that the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and the circumventricular organs are highly vascularized, allowing potential direct contact of HIV-1 with NSCs. Additionally, the “Trojan” T-cells and macrophages could possibly release viral particles directly onto NSCs, and also transmit the virus through the formation of immunological synapses with NSCs. Therefore, the central hypothesis in this dissertation is that NSCs may serve as a novel CNS reservoir through which HIV-1 infection persists, and subsequently lead to neurocognitive impairments through dysregulating adult neurogenesis. Adult neurogenesis is a dynamic process that describes the generation of new neurons and glial cells from NSCs and neural progenitor cells (NPCs). This process mainly takes place in two areas of the brain: the SVZ around the lateral ventricles, and the SGZ within the dentate gyrus of the hippocampus. New neurons generated in these two neurogenic niches integrate into their respective circuitries to modulate olfactory stimuli and aid in memory acquisition/consolidation processes. Most of previous studies on the role of HIV-1 in neurogenesis focused on single viral proteins rather than the entire integrated proviral genome, and did not correlate these neurogenic deficits to neurobehavioral outcomes. Therefore, the overall objective of the studies proposed in this dissertation is to further validate the feasibility and efficiency of HIV-1 infection in NSCs at both the in vitro and in vivo levels, and explore the correlation of HIV-induced adult neurogenic deficits with neurocognitive dysfunction. The first set of studies utilized an EcoHIV reporter virus to infect mouse NSCs both in vitro and in vivo. This was done because the native HIV-1 virus is incapable of infecting non-human cells, while EcoHIV has been engineered to infect murine cells using the gp80 envelope protein. Our initial studies revealed that EcoHIV preferentially infected NSCs rather than NPCs. Additionally, a 3-day live imaging study revealed that some NSCs were infected at different time points when compared to other cells. This raised credence to the possibility that these infected NSCs/NPCs were generating new viruses which were seeding new infection. NSCs were also capable of propagating higher levels of EcoHIV transcription after treatment with latency reversing agents. Furthermore, EcoHIV infection persisted in a small number of astrocytes during the differentiation process. Subsequent studies assessed whether differentiated neurons and glial cells were vulnerable to EcoHIV infection. Our studies showed that only a small percentage of astrocytes and oligodendrocytes were infected by EcoHIV. Throughout these studies, differentiated neurons were shown to be resistant to HIV-1 infection. These in vitro findings were further validated in vivo. Histological analysis revealed that NSCs were more vulnerable to EcoHIV infection than NPCs. Notably, a small percentage of neuroblasts harbored EcoHIV, though microglia cells were infected at a significantly higher number. Altogether, these findings further solidify NSCs as a novel reservoir through which HIV-1 infection can persist in the CNS. Such findings raised the possibility that HIV-1 in NSCs may dysregulate neurogenesis. The next set of studies in this dissertation elucidated the possible role of HIV-1 infection or viral protein productions in NSCs in regulating adult neurogenesis. Specific parameters analyzed included NSC quiescence, early-stage and middle-stage lineage differentiation, and late-stage neuronal maturation. We performed a series of in vitro and in vivo studies using the HIV-1 Tg26 transgenic mouse model, which mimics HIV-1 patients suffering from low-level and chronic stress from HIV-1 viral proteins in the ART era. NSC culture studies from HIV-1 Tg26 transgenic mice and their wild-type (WT) littermates revealed that Tg26 mouse NSCs were unable to form as many primary neurospheres as WT NSCs. Additionally, when the NSCs were stratified by size, Tg26 NSCs formed lower numbers of smaller-sized primary neurospheres and more larger-sized primary neurospheres. These findings demonstrated that low-level chronic HIV-1 infection robustly reduces the NSC pool, and hampers the initial differentiation process from NSCs to NPCs. In vitro differentiation analyses revealed that compared to WT NSCs, Tg26 NSCs had a lower propensity to differentiate towards a neuronal phenotype, and instead generated more astrocytes. These findings were further confirmed through in vivo hippocampal neural lineage analysis in the SGZs of both WT and Tg26 mice. Subsequent retroviral labeling studies in the SGZ revealed that newborn dentate granule neurons in Tg26 mice had lower dendritic complexity and decreased apical dendritic spine density, when compared to dentate granule neurons from WT mice. These studies further demonstrated that adult neurogenesis is dysregulated upon persistent HIV-1 challenge or infection in NSCs. Further studies sought to examine if HIV-1 Tg26 transgenic mice had any cognitive deficits. We specifically focused on middle-aged WT and Tg26 mice, since the HIV-1 patient population is increasing in age thanks to ART regimens, and thus are more susceptible to cognitive decline than younger HIV-1 patients. We also took into account the factor of biological sex into the behavioral studies. Five types of behavioral assessments revealed sex-specific deficits in Tg26 mice. Specifically, male Tg26 mice exhibited social novelty deficits, and short and long-term spatial memory impairments. On the other hand, female Tg26 mice only manifested spatial learning deficits and short-term spatial memory impairments. Both male and female Tg26 mice had preserved physiological and reflexive functioning, in addition to intact contextual and cued fear conditioning responses. We speculated that these sex-specific differences were due to defects in adult neurogenesis during aging. Through hippocampal neurogenic analysis, we showed that middle-aged male Tg26 mice had an accelerated depletion of the NSC pool and decreased number of neuroblasts. Middle-aged female Tg26 mice have decreased pools of NSCs and NPCs, as well as decreased number of neuroblasts. In conclusion, we have effectively demonstrated that HIV-1 is capable of infecting NSCs at relatively low efficiencies. While differentiated neurons were incapable of sustaining HIV-1 infection, a small percentage of differentiated astrocytes, oligodendrocytes, neuroblasts, and microglia were susceptible to infection. These results led us to investigate the role of dysregulated adult neurogenesis in HIV-1 Tg26 mice, and if this process led to the progression of HAND. Our comprehensive in vitro and in vivo studies demonstrated that HIV-1 induced NSC quiescence, inhibited neuronal differentiation, and promoted astroglial lineage differentiation. Additionally, newborn dentate granule neurons in Tg26 mice had lower dendritic complexity and dendritic spine densities. Finally, both male and female Tg26 mice had varying degrees of cognitive deficits, which was attributed to differing hippocampal neurogenic dynamics during the aging process. Further studies should explore how to restore the neurogenic process during aging in these Tg26 mice. Transcriptomic analysis, such as single cell RNA-sequencing studies, could also possibly assist in further understanding HIV-1 proviral expression changes in differing cellular types along the NSC lineage progression. / Biomedical Sciences

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years after injury. In this study we investigate the chronic consequences of TBI on adult neurogenesis and the possible involvement of chronic-inflammation in regulating adult neurogenesis. We used two popular TBI animal models, Control Cortical Impact (CCI) and Lateral Fluid Percussion Injury (LFPI) models, to examine focal and diffuse injury responses respectively. Adult rats received CCI, LFPI, or sham injury and were sacrificed at either 15 days or 3 months after injury to examine either subacute or chronic TBI-induced responses respectively. We found no change in levels of proliferation activity at both time points in both TBI models compared to sham animals. Using Doublecortin immunolabeling we found an enhanced generation of new neurons at 15 days after injury and by 3 months this activity was significantly reduced in both TBI models compared to sham animals. We also found persistent inflammation in the injured brains at both time points. Morphological assessment showed that LFPI model of TBI causes shrinkage of the ipsilateral hippocampus. Our results show that moderate TBI induced hippocampal neurogenesis in both models at the early time post-injury. However, at chronic stage, reduced hippocampal neurogenesis is observed in both models and this is accompanied by chronic inflammation. These results suggest that persistent inflammatory responses maybe detrimental to normal neurogenic activity, leading to cognitive impairment and neurodegeneration in long-term TBI survivors.

Le système constitué de la zone sous ventriculaire (ZSV) et du bulbe olfactif (BO) est l’une des deux régions cérébrales capables à l’âge adulte de produire de nouveaux neurones. La mise en évidence de cette neurogénèse adulte bulbaire a suscité un grand nombre d’interrogations quant à son rôle fonctionnel. Cependant les études réalisées dans ce domaine sont rares et contradictoires. L’objectif de cette thèse a été d’étudier l’impact de différentes expériences olfactives sur la neurogénèse afin de mieux comprendre son rôle fonctionnel. Nous avons choisi pour cela deux approches : d’une part l’étude de l’implication des néoneurones bulbaires lors de deux tâches d’apprentissage olfactif mettant en œuvre des odeurs neutres ; et d’autre part l’étude du rôle de ces néoneurones dans une situation de vie où l’olfaction joue un rôle primordial et où des variations de neurogénèse ont été rapportées: la maternité. Dans un premier temps, nous avons mis en évidence grâce à une stratégie d’anatomie fonctionnelle que les néoneurones de 5 semaines étaient recrutés lors d’un apprentissage de discrimination olfactive, mais pas lors de la restitution de cette information. Dans un deuxième temps, nous avons mis en évidence que la maternité améliorait les performances olfactives, et que cette amélioration était abolie par un stress gestationnel. Cependant, nous n’avons pas pu mettre en relation ces modifications de performances olfactives liées à la maternité et au stress avec des variations de neurogénèse. Nos travaux supportent l’hypothèse selon laquelle les néoneurones bulbaires sont impliqués dans la discrimination olfactive et mettent en évidence pour la première fois un impact de la maternité, qu’elle soit normale ou pathologique, sur les performances olfactives des mères. / In the mammalian brain, the subventricular zone (ZSV) and olfactory bulb (BO) system is a region where new neurons are continuously added throughout adulthood. While the functional consequences of continuous hippocampal neurogenesis have been extensively studied, the role of olfactory adult-born neurons remains more elusive. In particular, the involvement of these newborn neurons in odor discrimination and long-term odor memory is still a matter of debate. To address this question, we used two approaches. In the first one, we studied the recruitment of granular olfactory newborn neurons in two different tasks of olfactory learning with neutral odors. In the second one we studied the role of olfactory newborn neurons in a life situation where olfaction is crucial and where an increase in olfactory neurogenesis was reported, i.e. motherhood. In the first study, we found that odor discrimination learning recruited newborn neurons preferentially over preexisting ones, while odor memory restitution did not specifically activate newborn cells. Results of our second study indicate that motherhood improves olfactory memory and that this enhancement is abolished by a gestational stress. However, in our experimental conditions, we could not relate variations in neurogenesis with the modifications of olfactory performances linked to motherhood or stress. In conclusion our work brings new data in support of a functional role for newborn neurons in olfactory discrimination and shows for the first time an impact of motherhood, whether normal or pathological, on the olfactory performances of mothers.

Lensemble du travail de recherche réalisé s'est concentré sur l'évaluation du rôle fonctionnel que peut exercer le gène circadien Per2 sur les capacités de prolifération et différenciation des cellules souches/progénitrices à l'origine de la neurogenèse hippocampique. Ce travail a comporté d'une part, une cartographie phénotypique exhaustive de l'identité des cellules exprimant la protéine PER2 au sein de la structure hippocampique, et d'autre part une étude approfondie des conséquences de la l'invalidation de ce gène sur la régulation de la neurogenèse dans l'hippocampe de souris adultes. Dans la première partie de notre travail, nous avons démontré par une analyse immunohistochimique détaillée, qu'au niveau du gyrus dentelé (DG) de souris adultes, les cellules proliférantes exprimaient la protéine PER2 et que cette expression persistait dans les cellules de la lignée neuronale à différents stades de maturation. Par ailleurs, à l'inverse du noyau suprachiasmatique (centre générateur des rythmes circadiens), nous avons également pu observer une expression constante de cette protéine durant une période de 24h (Borgs et al, soumis). Dans la seconde partie de notre travail, nous nous sommes interrrogés sur le rôle fonctionnel que pouvait exercer le facteur de transcription circadien Per2 dans le DG de souris adultes. Nous avons montré que linvalidation de ce gène entraine dans le DG des souris déficientes pour la protéine PER2, une augmentation significative de la prolifération des progéntieurs neuronaux, ainsi que du nombre de neurones immatures. Cependant, nous navons observé aucune différence dans la génération de neurones matures (neurogenèse) entre le DG de souris sauvages et de souris invalidées pour Per2. Nos données ont révélé que le surplus de cellules en prolifération et de neurones immatures observés dans le DG de souris délétées pour Per2 apparaît donc totalement compensé par une augmentation de la mort cellulaire (Borgs et al, soumis). Pour étudier limplication fonctionnel de la protéine PER2 sur le contrôl de la prolifération de progéniteurs/cellules souches à lorigine de la neurogenèse adulte, nous avons mis au point la culture en suspension de cellules souches/progénitrices issues du DG post-natale de souris sauvages et déficientes pour Per2. Après 5 jours de culture, nous avons observé la formation de neurosphères dont la taille et dont la croissance était plus importante chez les souris déficientes pour Per2 que chez leurs homologues sauvages. Ce modèle de culture de DG nous a permis détudier de façon plus présice le destin cellulaire emprunté par les cellules proliférantes/souches dans le modèle muté, comparé au modèle sauvage. En condition de culture favorisant la différenciation, nous avons observé un plus grand nombre de neurones générés à partir des neurosphères issues de cellules de DG de souris mutées pour PER2. Ce modèle de culture de cellules progénitrices/souches issues du DG, confirme les résultats précédemment obtenus concernant le rôle de Per2 dans le contrôle de la prolifération et de la génération de nouveaux neurones in vivo. Parallèlement, nous avons tenté de déterminer si lexpression de Per2 pouvait exercer un rôle similaire au DG au sein de la zone sous ventriculaire antérieure (SVZ), la seconde zone où persiste de la neurogenèse tout au long de la vie. La SVZ du cerveau adulte représente un réservoir de progéniteurs proliférant qui vont cheminer le long dun courant rostral de migration pour atteindre le bulbe olfactif dans lequel ils vont se différencier en neurones. La protéine Per2 se révèle être exprimée dans les progéniteurs en prolifération exprimant Ki67. Tout comme dans le DG de souris adultes déficientes pour Per2, nous avons dénombré in vivo et in vitro une augmentation importante du nombre de cellules en prolifération comparé aux souris sauvages. Per2 semble donc être un des protagonistes impliqué dans la régulation de la prolifération et de la différenciation des progéniteurs/cellules souches à lorigine de la neurogenèse hippocampique.

Previous research on the relationship between spatial memory and adult hippocampal neurogenesis has been controversial. In the present study, neurogenesis was compared between two natural populations of the same species that differ in their reliance on spatial memory to cache and retrieve stored food. Western red squirrels store food in a single site whereas eastern red squirrels store food in multiple sites. Neurogenesis was assessed using endogenous markers of the number of proliferating cells (Ki-67) and the number of immature neurons (DCX), and neuronal recruitment was determined by measuring the area of the dentate gyrus of the hippocampus. The number of proliferating cells, immature neurons and neuronal recruitment were enhanced in the eastern compared to the western red squirrels, reflecting the food storing strategies used by the squirrels. This suggests that there is a positive correlation between adult hippocampal neurogenesis and spatial learning and memory.

Previous research on the relationship between spatial memory and adult hippocampal neurogenesis has been controversial. In the present study, neurogenesis was compared between two natural populations of the same species that differ in their reliance on spatial memory to cache and retrieve stored food. Western red squirrels store food in a single site whereas eastern red squirrels store food in multiple sites. Neurogenesis was assessed using endogenous markers of the number of proliferating cells (Ki-67) and the number of immature neurons (DCX), and neuronal recruitment was determined by measuring the area of the dentate gyrus of the hippocampus. The number of proliferating cells, immature neurons and neuronal recruitment were enhanced in the eastern compared to the western red squirrels, reflecting the food storing strategies used by the squirrels. This suggests that there is a positive correlation between adult hippocampal neurogenesis and spatial learning and memory.

Neurogenesis is the process of generation of neurons during embryonic development and adulthood. The focus of this doctoral work is the study of the cell biological aspects of neurogenesis and the mechanisms regulating the switch of neural stem cells from proliferation to differentiation. During embryonic development neurogenic divisions occur at the apical or basal side of the pseudostratified epithelium that forms the wall of the neural tube, the neuroepithelium. Apical asymmetric neurogenic divisions (AP) give rise to a neuron and a progenitor cell, while basal symmetric neurogenic divisions (BP) give rise to two neurons. The first part of this thesis is focused on the study of some cell biological aspects of BPs. We first validated the use of the Tis21-GFP knock in mouse line, previously generated in our laboratory. We found that the totality of neurogenic progenitors is marked by the expression of a nuclear GFP. We calculated the abundance of BPs overtime since the onset of neurogenesis showing that BPs overcome APs over development. We studied the loss of apical contact of the basal dividing cells. We found that both neurogenic and non-neurogenic basally dividing progenitors miss the apical contact; which is lost prior mitosis. We generated and characterized a second mouse line, the Tubb3-GFP line expressing a plasma membrane-localized GFP in neurons. These two lines were crossed to obtain a new line (TisTubb-GFP) allowing detection of neurogenic divisions and tracking daughter cells. Using this model: (i) we imaged symmetric neurogenic divisions of BPs, identifying daughter cells as neurons, during imaging; (ii) we compared the kinetics of betaIII-tubulin-GFP appearance after apical or basal mitosis, showing that daughters of BPs express betaIII-tubulin-GFP faster than daughters coming from apical divisions; (iii) we imaged neuronal migration and localization of the Golgi apparatus. Neurogenesis in the adult is confined to two specific regions in the telencephalon: the sub ependymal zone, lining the ventricle, and dentate gyrus of the hippocampus. The second part of this thesis focuses on the adult neurogenic progenitors lineage. Tis21-GFP expression was found and characterized in the two adult neurogenic regions from early postnatal to adulthood. Using a panel of markers for the adult neurogenic cell lineage and confocal imaging, we characterized Tis21-GFP expression, in the dentate gyrus. Tis21-GFP is first expressed in the neurogenic subpopulation of doublecortin positive cells. Tis21-GFP is inherited by the neurons and eventually degraded. Moreover, our data suggest that mitotic Tis21-GFP cells are an indicator of the levels of neurogenesis more accurate than doublecortin positive cells, in the early postnatal mouse. (Anlage Quick time movies 77,88 MB)

Adult hippocampal neurogenesis is regulated at various levels and by various factors. Genetic influence is an important key determinant of adult neurogenesis and exerts its effects at all levels. In vivo studies have suggested that adult hippocampal neurogenesis is highly variable and heritable among different laboratory strains of mice. To dissect the genetic effect from other contributing factors, it is necessary to study adult neurogenesis under highly controlled environment conditions. We extracted adult hippocampal precursor cells (AHPCs) from 20 strains of the BXD set of recombinant inbred mice, cultured them and studied the effect of genetic background on neurogenesis. The BXD panel consists of mouse lines derived from an intercross between inbred parentals C57BL/6J and DBA/2J. Both of the parentals are fully sequenced and all the strains are well characterized in terms of genotypic and phenotypic characteristics. This allows us to use advanced genetic techniques to identify novel genomic loci and gene-gene interactions important in adult neurogenesis. Comparison of the AHPCs from 20 BXD strains, with respect to cell proliferation and neuronal and astrocytic differentiation in vitro, revealed a large variation for these traits across the strains. Proliferation, as measured by BrdU incorporation, showed over two- fold differences between the extremes. Similar differences were observed for neurogenic (4-fold) and astrogenic differentiation (2-fold). These three traits all showed strong heritability values indicating that the differences were mainly attributed to the genetic component. QTL mapping, with these phenotypic data, revealed that there was no major contribution from single loci controlling these traits. Instead, we found many loci with smaller effects associated with these traits. Gene expression profiling using RNA samples from proliferating cultures of the 20 BXD mice strains yielded two cis eQTL candidates that directly regulated proliferation, LRP6 and Chchd8. LRP6 is well known as a co-receptor of Wnt signaling, but the function of Chchd8 is not known. Further experimentation, using over expression and gene silencing demonstrated that LRP6 negatively regulates AHPCs proliferation. Thus, from this study using a system genetics approach, we were able to identify, LRP6 as a novel regulator of adult hippocampal neurogenesis.

La neurogenèse adulte permet la formation de nouveaux neurones dans les bulbes olfactifs de la souris. Les propriétés des cellules souches neurales situées dans la zone sous-ventriculaire (ZSV) et des précurseurs sont régulées par la niche contenant des cellules de support et une matrice extracellulaire (MEC). Des facteurs contenus dans le liquide cérébrospinal (LCS), produits par les plexus choroïdes (PC), contrôlent aussi la niche. L'homéoprotéine Otx2 est secrétée dans le LCS par les PC, et internalisée spécifiquement par certaines cellules du parenchyme cérébral. Otx2 est impliquée dans différentes étapes du développement du cerveau, dont celui des PC, et peut agir de manière non-cellulaire-autonome. Ma thèse vise à comprendre comment Otx2 régule les fonctions des PC et participe à la neurogenèse adulte. Grâce à des études génomiques d'un modèle murin knockdown (KD) d'Otx2 dans les PC adultes, nous avons montré que (i) les PC de différents ventricules présentent des profils d'expression différents (ii) le KD d'Otx2 modifie l'expression de gènes impliqués dans des fonctions importantes des PC (iii) la dérégulation de certains gènes après KD est spécifique d'un type de PC. Une étude protéomique suggère (iv) qu'Otx2 pourrait être impliquée à d'autres niveaux que la régulation transcriptionnelle. L'étude de la neurogenèse adulte dans des modèles murins KD d'Otx2 nous a permis de montrer que (i) l'expression d'Otx2 dans les PC régule la neurogenèse adulte (ii) Otx2 transfère dans les astrocytes de la ZSV (iii) le transfert d'Otx2 est suffisant pour réguler la neurogenèse (iv) le KD d'Otx2 dans les PC modifie l'expression de protéines de la MEC secrétées par les astrocytes. / Adult neurogenesis in mice involves neural stem cells in the subventricular zone (SVZ) whose progenitors integrate into the olfactory bulbs. The neurogenic niche, which contains supporting cells and extracellular matrix (ECM), regulates the properties (proliferation, migration and differentiation) of progenitor cells. This niche is influenced by factors from cerebrospinal fluid (CSF), which is produced by the choroid plexus (CP) in the brain ventricles. The Otx2 homeoprotein transcription factor is secreted into CSF by CP, and taken up by a specific subset of cells within the brain parenchyma. Otx2 is involved in various stages of brain development, including CP development, and has non-cell autonomous functions. The aim of my thesis is to understand how Otx2 regulates adult CP function and participates in adult SVZ neurogenesis. Through genomic studies, we investigated the consequence of Otx2 knockdown (KD) in adult CP and found: (i) adult CP from different ventricles exhibit different expression profiles; (ii) Otx2 KD alters the expression of genes with important CP functions; and (iii) deregulation of certain genes after Otx2 KD can be CP specific. Through proteomics studies, we found that (iv) adult Otx2 could be involved in functions beyond transcriptional regulation, such as RNA processing.To evaluate the role of Otx2 in SVZ neurogenesis, we also used Otx2 KD mouse models. We found that: (i) the expression of Otx2 in CP regulates adult neurogenesis; (ii) Otx2 transfers to astrocytes of the SVZ; (iii) Otx2 transfer is sufficient to regulate adult neurogenesis; and (iv) Otx2 KD in CP alters the expression of ECM proteins secreted by astrocytes in the neurogenic niche.